Cytokine-Targeted Therapeutics for KSHV-Associated Disease
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viruses Review Cytokine-Targeted Therapeutics for KSHV-Associated Disease Nedaa Alomari and Jennifer Totonchy * Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA; [email protected] * Correspondence: [email protected] Received: 1 September 2020; Accepted: 25 September 2020; Published: 28 September 2020 Abstract: Kaposi’s sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus 8 (HHV-8), is linked to several human malignancies including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman’s disease (MCD) and recently KSHV inflammatory cytokine syndrome (KICS). As with other diseases that have a significant inflammatory component, current therapy for KSHV-associated disease is associated with significant off-target effects. However, recent advances in our understanding of the pathogenesis of KSHV have produced new insight into the use of cytokines as potential therapeutic targets. Better understanding of the role of cytokines during KSHV infection and tumorigenesis may lead to new preventive or therapeutic strategies to limit KSHV spread and improve clinical outcomes. The cytokines that appear to be promising candidates as KSHV antiviral therapies include interleukins 6, 10, and 12 as well as interferons and tumor necrosis factor-family cytokines. This review explores our current understanding of the roles that cytokines play in promoting KSHV infection and tumorigenesis, and summarizes the current use of cytokines as therapeutic targets in KSHV-associated diseases. Keywords: KSHV; pathogenesis; cytokine signaling; cytokine therapeutics; cytokine targeted therapy; immunomodulatory therapeutics 1. Introduction In 1994, Kaposi’s sarcoma-associated herpesvirus (KSHV) was first identified in a Kaposi’s sarcoma (KS) lesion by Chang and Moore [1]. KS is a highly proliferative tumor derived from lymphatic endothelial cells [2]. KSHV infection is also linked to two B cell lymphoproliferative disorders—primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [3,4]. In addition, recent studies have demonstrated a third KSHV-associated disease. KSHV-associated inflammatory cytokine syndrome (KICS) is characterized by high levels of viral interleukin-6 (vIL6) or human IL-6 (hIL-6) [5]. Cytokine production has been shown to contribute to KS pathogenesis [6–8]. In fact, high levels of IL-6, TNF-α and IL-10 were identified in sera of KS patients [9] and KS tumors have shown elevated level of IL-6, IL-10 and IFN-γ [10]. Furthermore, in vitro studies have reported that high production of proinflammatory cytokines, such as IL-6, TNF-α, CCL-2 and, CXCL-10, may contribute to the progression of KS [11–18]. One of the mechanisms that may trigger KSHV reactivation, is the secretion of inflammatory cytokines, through activation of Toll-like receptors 7 and 8 (TLR7/8), oncostatin M (OSM), hepatocyte growth factor (HGF) and secretion of interferon-γ (IFN-γ) when stimulated by co-infection with other viruses [19,20]. Previous reports have also shown that KSHV infection induces proinflammatory cytokines including IL-1a, IL-1b, which are implicated in the pathogenesis of KSHV-associated malignancies [21,22]. Cytokines are soluble messengers controlling immune responses, and are involved in myriad biological process including inflammation, cell proliferation and cell migration. Manipulation of Viruses 2020, 12, 1097; doi:10.3390/v12101097 www.mdpi.com/journal/viruses Viruses 2020, 12, 1097 2 of 18 cytokines may have therapeutic benefit in diseases ranging from cancer to autoimmune manifestations and infectious disease. Multiple recombinant cytokines have been approved by the Food and Drug Administration (FDA) including IL-2 for the treatment of advanced renal cell carcinoma (RCC) [23] and IFN-α for the treatment of hairy cell leukemia [24] and Acquired immunodeficiency syndrome (AIDS)-related Kaposi’s sarcoma [25]. Development of cytokine-based therapies that target immunomodulatory mechanisms may be promising treatments for KSHV-associated diseases. Indeed, tocilizumab, the first humanized IL-6 receptor blocking antibody, has been approved for treatment of MCD in Japan. As knowledge of KSHV-associated diseases has grown, the research and the clinical trials have expanded to include cytokine targeted therapeutics (Table1). Table 1. Summary of the clinical trials referenced in this review. Summary Cytokine KSHV Disease Drug Dose Study Type of the Result Alleviated the Open-label trial inflammatory 8 mg/kg MRA in 28 patients for 16 symptoms and Tocilizumab biweekly weeks [43] biochemical IL-6 MCD abnormalities Ongoing Phase II 8 mg/kg every 2 clinical trial weeks (NCT01441063). One patient had complete clinical benefit response and four patients had Tocilizumab 8 mg/kg IV on day 1 partial clinical of 14-day cycles for a benefit responses on maximum of 6 cycles Open label, single tocilizumab alone. center pilot study Three patients who Zidovudine 600mg every 6 h [45] had AZT/VGC in combination with Valganciclovir 900mg every 12 h tocilizumab, two had partial clinical benefit responses and one had complete clinical benefit response Cohorts 1 to 5 enrolled in sequential order. 18 out of 23 patients 2-h infusion at 3 had clinical benefits mg/kg every 2 weeks, response and 12 6 mg/kg every 2 patients showed weeks, 12 mg/kg objective tumor every 3 weeks, 6 Phase I, open-label, response. 11 patients mg/kg weekly, and dose-finding and Siltuximab treated with the 12 mg/kg every 2 seven-cohort study highest dose of 12 weeks, respectively. in 23 patients [46] mg/kg had clinical benefit response and Cohort 6, 1-h 8 patients showed infusion at 12 mg/kg objective tumor every 3 weeks. response Cohort 7, 9 mg/kg every 3 weeks. Randomized, 11 mg/kg double-blind, 18 of 53 had tumor intravenous infusion placebo-controlled and symptomatic every 3 weeks trial in 79 patients responses [47]. Viruses 2020, 12, 1097 3 of 18 Table 1. Cont. Summary Cytokine KSHV Disease Drug Dose Study Type of the Result Anti-viral effects Starting dose 35 106 Open therapeutic AIDS-KS IFNa × Anti-tumor response IFNa Reduced to 5–10 106 trial [92] × in 38% of patients 1 million (low dose) or 10 million IFNa with (intermediate dose) randomized phase II AIDS-KS 40% tumor response didanosine IU per day by clinical trials [93] subcutaneous (s.c.) injection. Improved the clinical manifestation Phase II 8 out of 17 patients 100 mg/day for 12 TNFa AIDS-KS Thalidomide dose-escalation achieved partial months study [120] response and 2 patients had stable conditions 16 patients. Achieved objective phase I/II study tumor response and AIDS-KS and 5 mg/day for 21/28 in 22 KS patients Pomalidomide 9 out of 15 HIV KS days with and without infected patients. HIV infection. [121] Achieved objective response. 17 had a complete or 100, 300, 500 and 625 Phase 1 pilot study partial KS tumor AIDS-KS L12 ng/kg [129] response (61%) with IL-12 three highest does. 300 ng/kg subcutaneously IL12 alone and twice weekly for six 83.3% complete or in combination Phase II clinical trial AIDS-KS 3-week cycles, partial KS tumor with pegylated [130] followed by 500 response. liposomal ng/kg subcutaneous IL-12 twice weekly Ongoing Phase I/II Advanced KS NHS-IL12 clinical trial (NCT04303117) 2. IL-6 Interleukin-6 is an inflammatory cytokine with pleiotropic effects produced by many cells in the body, such as epithelial cells, muscle cells, hematopoietic cells and stromal cells. It plays a role in various biological processes, including cancers and immune system diseases [26,27]. In the early stages of inflammation, monocytes, and macrophages secret IL-6 in response to activation of Toll-like receptors. Upregulation and persistent IL-6 stimulation are observed in in several inflammatory and autoimmune diseases [28]. The KSHV K2 gene [29] encodes a protein, viral IL-6 (vIL-6), that shares 24.8% amino acid similarity with human interleukin-6 (hIL-6) [29,30]. Several studies have uncovered roles of vIL-6 in KSHV-associated diseases, reviewed in [31]. Recently, a new in silico study presented the significant similarity between vIL6 and hIL6 folding and used this analysis to describe the similarity of the functions or interactions of both proteins, and defined four amino acid to be a new target to inhibit the pathological role of vIL6 [32]. A recent pilot study in 25 children with human immunodeficiency viruses (HIV)-associated KS in Malawi has demonstrated associations between KSHV viral load and hIL-6 levels in the blood, which may contribute to disease progression. [33]. Expression of vIL-6 protein has been detected in serum from patients with KS, PEL and MCD [34], and high levels of plasma hIL-6 drive progression of MCD and correlate with poor prognosis in PEL [35]. Moreover, experiments performed in AIDS/KS-derived cells demonstrated that hIL-6 is required for tumor cell proliferation [11]. vIL-6 can also serve as autocrine growth factor for PEL cell lines [36], and induces vascular endothelial growth factor (VEGF) in vitro and in vivo which plays a major role in PEL pathogenesis [37]. In addition, a study has reported that Tocilizumab, inhibited Viruses 2020, 12, 1097 4 of 18 ascites formation in the BCBL-1 intraperitoneal xenograft mouse model of PEL [38], suggesting that hIL-6 is a viable therapeutic target in PEL. Patients with KICS, show elevated levels of hIL- 6 and vIL-6 [5]. KICS is one of the most aggressive clinical manifestations linked to KSHV infection, and it is associated with cytokine storm including high levels of hIL-6 [5], due to the overproduction of hIL-6 with high KSHV viral load it is most likely to contribute to the clinical features of the disease. Moreover, there is significant crosstalk between vIL-6 and hIL-6. vIL-6 can induce endogenous hIL-6 secretion in patients with MCD [39].